Chromosome 10q24.32 Variants Associate With Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

BACKGROUND: Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown. METHODS AND RESULTS: The authors studied 4150 participants from 6 geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome-wide association study revealed 14 variants at one locus associated with global BAD at genome-wide significance (P<5×10-8) (top single-nucleotide polymorphism, rs7921574; ß=0.06 [P=1.54×10-8]). This locus mapped to an intron of CNNM2. A trans-ancestry genome-wide association study meta-analysis identified 2 more loci at NT5C2 (rs10748839; P=2.54×10-8) and AS3MT (rs10786721; P=4.97×10-8), associated with global BAD. In addition, 2 single-nucleotide polymorphisms colocalized with expression of CNNM2 (rs7897654; ß=0.12 [P=6.17×10-7]) and AL356608.1 (rs10786719; ß=-0.17 [P=6.60×10-6]) in brain tissue. For the posterior BAD, 2 variants at one locus mapped to an intron of TCF25 were identified (top single-nucleotide polymorphism, rs35994878; ß=0.11 [P=2.94×10-8]). For the anterior BAD, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10-8). CONCLUSIONS: The current study reveals 3 novel risk loci (CNNM2, NT5C2, and AS3MT) associated with BADs. These findings may help elucidate the mechanism by which BADs may influence cerebrovascular health.

Chromosome 10q24.32 Variants Associate with Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

Background: Brain arterial diameters are novel imaging biomarkers of cerebrovascular disease, cognitive decline and dementia. Traditional vascular risk factors have been associated with brain arterial diameters but whether there may be genetic determinants of brain arterial diameters is unknown. Results: We studied 4150 participants from six geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). We measured brain arterial diameters for 13 segments and averaged them to obtain a global measure of brain arterial diameters as well as the posterior and anterior circulations. A genome-wide association study (GWAS) revealed 14 variants at one locus associated with global brain arterial diameter at genome-wide significance (P<5×10-8) (top SNP, rs7921574; ß =0.06, P=1.54×10-8). This locus mapped to an intron of CNNM2. A trans-ancestry GWAS meta-analysis identified two more loci at NT5C2 (rs10748839; P=2.54×10-8) and at AS3MT (rs10786721; P=4.97×10-8), associated with global brain arterial diameter. In addition, two SNPs co-localized with expression of CNNM2 (rs7897654, ß=0.12, P=6.17×10-7) and AL356608.1 (rs10786719, ß =-0.17, P=6.60×10-6) in brain tissue. For the posterior brain arterial diameter, two variants at one locus mapped to an intron of TCF25 were identified (top SNP, rs35994878; ß =0.11, P=2.94×10-8). For the anterior brain arterial diameter, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10-8). Conclusion: Our study reveals three novel risk loci (CNNM2, NT5C2 and AS3MT) associated with brain arterial diameters. Our finding may elucidate the mechanisms by which brain arterial diameters influence the risk of stroke and dementia.

A population-based meta-analysis of circulating GFAP for cognition and dementia risk.

OBJECTIVE: Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population-based level are necessary to broaden generalizability to community settings. METHODS: Circulating GFAP levels were assayed using a Simoa HD-1 analyzer in 4338 adults without prevalent dementia from four longitudinal community-based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all-cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta-analysis was performed on the estimates derived from each cohort using random-effects models. RESULTS: Meta-analyses indicated that higher circulating GFAP associated with lower general cognition (ß = -0.09, [95% confidence interval [CI]: -0.15 to -0.03], p = 0.005), but not with total brain or hippocampal volume (p > 0.05). However, each standard deviation unit increase in log-transformed GFAP levels was significantly associated with a 2.5-fold higher risk of incident all-cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52-4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42-4.53]) over up to 15-years of follow-up. INTERPRETATION: Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.

Polygenic Risk, Midlife Life's Simple 7, and Lifetime Risk of Stroke.

Background Recent genetic discoveries in stroke have unleashed the potential of using genetic information for risk prediction and health interventions aimed at disease prevention. We sought to estimate the lifetime risk of stroke (LTRS) by levels of genetic risk and to investigate whether optimal cardiovascular health can offset the negative impact of high genetic risk on lifetime risk of stroke. Methods and Results Study participants were 11 568 middle-aged adults (56% women, 23% Black adults), who were free of stroke at baseline and were followed up for a median of 28 years. The remaining LTRS was estimated according to levels of genetic risk based on a validated stroke polygenic risk score, and to levels of cardiovascular health based on the American Heart Association Life's Simple 7 recommendations. At age 45, individuals with high, intermediate, and low polygenic risk score had a remaining LTRS of 23.2% (95% CI, 20.8%-25.5%), 13.8% (95% CI, 11.7%-15.8%), and 9.6% (95% CI, 7.3%-11.8%), respectively. Those with both a high genetic risk and an inadequate Life's Simple 7 experienced the highest LTRS: 24.8% (95% CI, 22.0%-27.6%). Across all polygenic risk score categories, those with an optimal Life's Simple 7 had a ≈30% to 43% lower LTRS than those with an inadequate Life's Simple 7. This corresponded to almost 6 additional years lived free of stroke. Conclusions The LTRS varies by levels of polygenic risk and cardiovascular health. Maintaining an optimal cardiovascular health can partially offset a high genetic risk, emphasizing the importance of modifiable risk factors and illustrating the potential of personalizing genetic risk information to motivate lifestyle changes for stroke prevention.

Pityriasis rubra pilaris type 6: A case report in an AIDS patient.

A 24-year-old woman, known to be human immunodeficiency virus positive for 6 years, presented with an itchy rash on the body. She had dull erythematous to hyperpigmented scaly plaques over the body, with extensor predominance. Inflammatory papules and nodules were noted on the face. Follicular hyperkeratotic papules were seen on the shins, giving a "nutmeg grater" feel. All her nails were dystrophic. Histopathology was consistent with the clinical diagnosis of pityriasis rubra pilaris. CD4 counts had dropped to 192 cells/µl, so she was started on antiretroviral therapy along with acitretin to which she responded well within 2 months.

Association of blood pressure with cognitive function at midlife: a Mendelian randomization study.

BACKGROUND: Whether high blood pressure has a causal effect on cognitive function as early as middle age is unclear. We investigated whether high blood pressure (BP) causally impairs cognitive function at midlife using Mendelian Randomization (MR). METHODS: We applied a two-sample MR approach to investigate the causal relationship between BP and midlife cognitive performance measured by the Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), and Stroop Interference test. We used a total of 109 genetic polymorphisms with established associations with BP as instrumental variables and estimated gene-cognitive function association in 1369 middle-aged adults (Mean age (SD): 50.8 (3.3), 54.0% women) from the CARDIA study. RESULTS: A 10 mmHg increment in genetically-predicted systolic, diastolic, or pulse pressure was associated with a 4.9 to 7.7-point lower DSST score (P = 0.002, SBP; P = 0.005, DBP and P = 0.008, PP), while a 10 mmHg increment in genetically-predicted SBP was associated with a 0.7 point lower RAVLT and a 2.3 point higher Stroop (P = 0.046 and 0.011, respectively). CONCLUSIONS: This MR analysis shows that high BP, especially SBP, is causally associated with poorer processing speed, verbal memory, and executive function during midlife. These findings emphasize the need for further investigation of the role and mechanisms of BP dysregulation on cognitive health in middle age and perhaps, more broadly, across the lifespan.

Vasopressor treatment and mortality following nontraumatic subarachnoid hemorrhage: a nationwide electronic health record analysis.

OBJECTIVE: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular condition, not only due to the effect of initial hemorrhage, but also due to the complication of delayed cerebral ischemia (DCI). While hypertension facilitated by vasopressors is often initiated to prevent DCI, which vasopressor is most effective in improving outcomes is not known. The objective of this study was to determine associations between initial vasopressor choice and mortality in patients with nontraumatic SAH. METHODS: The authors conducted a retrospective cohort study using a large, national electronic medical record data set from 2000-2014 to identify patients with a new diagnosis of nontraumatic SAH (based on ICD-9 codes) who were treated with the vasopressors dopamine, phenylephrine, or norepinephrine. The relationship between the initial choice of vasopressor therapy and the primary outcome, which was defined as in-hospital death or discharge to hospice care, was examined. RESULTS: In total, 2634 patients were identified with nontraumatic SAH who were treated with a vasopressor. In this cohort, the average age was 56.5 years, 63.9% were female, and 36.5% of patients developed the primary outcome. The incidence of the primary outcome was higher in those initially treated with either norepinephrine (47.6%) or dopamine (50.6%) than with phenylephrine (24.5%). After adjusting for possible confounders using propensity score methods, the adjusted OR of the primary outcome was higher with dopamine (OR 2.19, 95% CI 1.70-2.81) and norepinephrine (OR 2.24, 95% CI 1.80-2.80) compared with phenylephrine. Sensitivity analyses using different variable selection procedures, causal inference models, and machine-learning methods confirmed the main findings. CONCLUSIONS: In patients with nontraumatic SAH, phenylephrine was significantly associated with reduced mortality in SAH patients compared to dopamine or norepinephrine. Prospective randomized clinical studies are warranted to confirm this finding.

Scleromyxedema: An Atypical Case.

Scleromyxedema is a rare, chronic and persistent idiopathic disorder characterized by a generalized papular eruption due to dermal mucin deposition with an increase in dermal collagen. Patients usually have associated paraproteinemia. We describe the case of a 59-year-old gentleman with features of scleromyxedema, who had severe pruritus, scalp involvement, unrestricted mobility and associated peripheral eosinophilia, but no monoclonal gammopathy.

Levocetirizine and rupatadine in chronic idiopathic urticaria.

BACKGROUND: Chronic idiopathic urticaria (CIU) is a common dermatological condition. Its pathogenesis involves mainly histamine and also other mediators, including platelet-activating factor (PAF) and tumor necrosis factor-α (TNF-α). In the absence of an exact etiology, H1 -antihistaminics are the mainstay of treatment. Levocetirizine is widely prescribed for CIU. Rupatadine, a newer antihistaminic, has PAF receptor antagonist activity and has shown anti-TNF-α activity in vitro. These additional anti-inflammatory effects may improve its efficacy. OBJECTIVES: This study was conducted to compare the efficacy and safety of rupatadine and levocetirizine, respectively, in CIU patients. METHODS: A prospective, open, comparative, randomized study was conducted in 100 patients, of whom 50 were treated with levocetirizine and 50 were treated with rupatadine. Efficacy parameters used were urticarial activity score (UAS) and Dermatology Life Quality Index (DLQI) values. Safety was evaluated by monitoring for adverse drug reactions and by using the critical flicker fusion threshold (CFFT) test and a visual analog scale (VAS) at baseline, and at 2, 4, and 6 weeks. RESULTS: The mean UAS decreased to 0.10 in the levocetirizine group and to 0.38 in the rupatadine group. Patients in the levocetirizine group showed a more significant (P < 0.001) improvement, although symptoms improved in both groups. Significant reductions in mean DLQI scores were observed in both groups, but the decrease was statistically significant in the levocetirizine group (P < 0.05). Somnolence was the most common side effect in both groups. Patients in the levocetirizine group showed more psychomotor impairment based on the CFFT test. Findings on the VAS showed sedative effects in both groups (P < 0.05). CONCLUSIONS: Levocetirizine was found to be more efficacious than rupatadine in CIU patients, but both drugs caused mild sedation.

ARTSENS - an image-free system for noninvasive evaluation of arterial compliance.

Evaluation of arterial compliance is significant in cardiovascular diagnosis for early detection of coronary heart disease. We present ARTSENS, an image-free system for non-invasive evaluation of arterial compliance in-vivo. The system utilizes a single element ultrasound probe with intelligent measurement algorithms to ensure accurate evaluation of local arterial compliance without an image. The ability of the system to detect artery anatomy and measure compliance was verified by in-vivo measurements conducted on 106 subjects. The accuracy of compliance estimates were evaluated by comparison with a state of art imaging system. The measurements made using ARTSENS showed strong correlation with those made using the imaging system. The ability of ARTSENS to detect age-related trends in arterial compliance was also investigated.

Mucocutaneous manifestations of Dengue fever.

Dengue viral infection is a cause of considerable morbidity and mortality and may be associated with a variety of mucocutaneous manifestations that may provide important early clues to the diagnosis of this condition. Cutaneous and mucosal findings like confluent erythema, morbilliform eruptions, and hemorrhagic lesions may figure prominently in the clinical features of dengue. The differential diagnoses include a large number of bacterial and viral exanthems as well as drug rash.

Alopecia areata and autoimmunity: a clinical study.

Alopecia areata (AA) frequently occur in association with other autoimmune diseases such as thyroid disorders, anemias and other skin disorders with autoimmune etiology. Despite numerous studies related to individual disease associations in alopecia areata, there is paucity of literature regarding comprehensive studies on concomitant cutaneous and systemic diseases. The present study has been designed to determine if there is a significant association between alopecia areata and other autoimmune diseases. This study covers 71 patients with the diagnosis of alopecia areata as the case group and 71 patients with no evidence of alopecia areata as the control group. Among the cutaneous diseases associated with AA, atopic dermatitis (AD) showed maximum frequency with an O/E ratio of 2.5, which indicates that it is two to three times more common in patients with alopecia areata. In our study, thyroid disorders showed the highest frequency with on O/E ratio of 3.2 and a P value of 0.01, which is statistically highly significant. Among the thyroid disorders, hypothyroidism was the most frequent association (14.1%) in our study. Since systemic involvement is not infrequent in patients with alopecia areata, it is imperative to screen these patients for associated disorders, particularly atopy, thyroid diseases, anemias and other autoimmune disorders, especially if alopecia areata is chronic, recurrent and extensive.

Cutaneous manifestations of dengue viral infection in Punjab (north India).

BACKGROUND: Dengue infection is emerging as a public health problem in India. Despite numerous studies, there is a paucity of literature regarding the cutaneous manifestations of dengue. This study was performed to investigate the prevalence and type of cutaneous manifestations in dengue viral infection. METHODS: Two hundred and fifty-six patients with febrile illness, admitted to the Christian Medical College and Hospital, Ludhiana, India, were studied. On the basis of the clinical criteria and laboratory tests, 124 patients were diagnosed with dengue viral infection, and these patients were investigated in detail. Serologic tests were attempted in only 84 patients, and all of these samples tested positive for anti-dengue immunoglobulin M (IgM) antibodies. RESULTS: Of the 124 patients with dengue infection, 41 (23.1%) were classified with dengue fever (DF) and 83 (66.9%) with dengue hemorrhagic fever (DHF), four (3.2%) of whom had dengue shock syndrome (DSS). Cutaneous involvement was seen in 46.8% of patients, the most common symptom being maculopapular/morbilliform eruption (48.3%), followed by ecchymotic (27.6%), petechial (13.8%), and macular/scarlatiniform (10.3%) eruption. Maculopapular eruption was observed more in DF, whereas petechiae, ecchymosis, and mucosal involvement were seen more in DHF; 72.4% of patients with cutaneous manifestations were asymptomatic, and 27.6% had pruritus. Involvement was generalized in 48.3% of patients, with the limbs and trunk involved in 32.8% and 18.9% of patients, respectively. Mucosal involvement was seen in 29.8% of patients, with conjunctival involvement being the most common (20.9%), followed by the lips (4.8%), palate (2.4%), and tongue (1.6%). CONCLUSIONS: This study describes the variety of cutaneous features associated with dengue viral infection which may evolve during the course of the disease. As a significant proportion of patients showed cutaneous features, these manifestations, together with simple laboratory tests, will be helpful in the early diagnosis of dengue viral infection.